Renin passes from the kidneys into the blood where it affects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
With compounds such as (with INN name) aliskiren ((2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide), a new antihypertensive has been developed which interferes with the renin-angiotensin system at the beginning of angiotensin II biosynthesis.
As the compound comprises 4 chiral carbon atoms, the synthesis of the enantiomerically pure compound is quite demanding. Therefore, amended routes of synthesis that allow for more convenient synthesis of this sophisticated type of molecules are welcome.
It is therefore a problem to be solved by the present invention to provide new synthesis routes and new intermediates allowing a convenient and efficient access to this class of compounds.
In the search for more convenient ways to manufacture renin inhibitors such as aliskiren, it was found that pyrrolidines as shown below and derivatives thereof can be very useful intermediates in the synthesis of such renin inhibitors.
wherein    R is hydrogen, alkyl or alkoxyalkyl;    R1 is hydrogen, alkyl or alkoxyalkyl;    Ry is hydrogen or preferably a hydroxyl protecting group;    Rz is hydrogen or unsubstituted or substituted alkyl; and    PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl or benzyloxycarbonyl.
These pyrrolidines and methods to synthesize renin inhibitors are described in detail in GB application no. 0511686.8 and in the resulting PCT application PCT/EP2006/005370. The pyrrolidine ring locks the stereochemistry for subsequent conversions yielding eventually the amine and hydroxy moieties with the desired stereochemistry. However, although this process works well and has certain advantages, the pyrrolidine intermediates are prepared from amino alcohol compounds of the following formula

These compounds are accessible using a rather lengthy synthesis starting from pyroglutamic acid. Reference is made to PCT application EP2005/009347 published as WO2006/024501 where ketone amino derivatives of such compounds are prepared that can be converted into the respective amino alcohol.